B cells play a central role in acquired immunity. These cells possess the unique ability to mount a rapid and directed antibody (Ab) response against foreign antigens (Ag), and to act as Ag presenting cells. To maintain B cell homeostasis and a self-tolerant state, it is necessary to generate a continuous pool of B cell precursors that will mature and migrate to peripheral organs, as well as maintain a process of negative selection to eliminate autoreactive B cells. Dysregulation in the B cell developmental process could lead to a block in B cell development, and thus immune deficiency, or conversely, to an escape and expansion of self-reactive B cells leading to autoimmunity.
Generation of high affinity, somatically hypermutated autoantibodies is one of the hallmarks of autoimmune conditions. The autoantibodies can cause severe tissue damage (e.g., as in lupus nephritis) or loss of blood components (e.g., as in immune thrombocytopenia purpura). The prevailing treatment strategies for autoimmune disorders employ global immunosuppressants that have harmful side effects with long-term use.
Recent discovery of the B cell survival and maturation factor BAFF (also known as TALL-1, THANK, BLyS, zTNF4, and TNFSF13B) provided a unique opportunity for developing targeted intervention strategies for autoreactive B cell function. Elucidation of the role of BAFF in acquired immunity has been rapid since its first description as a B cell growth factor. BAFF (Accession No. AAD25356) is described in, e.g., Schneider et al (1999) J. Exp. Med., 189:1697-1710; PCT Publication WO 99/12964 and U.S. patent application Ser. No. 09/911,777. Studies have indicated that higher than normal levels of BAFF may contribute to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. For a review, see, e.g., Mackay et al. (2002) Nature Reviews: Immunology, 2:465-475; Kalled et al. (2003) Expert Opin. Ther. Targets, 7(1):115-23.
BAFF has been implicated in costimulation of B cells (Moore et al. (1999) Science, 285:260-263; Schneider et al. (1999) J. Exp. Med., 189:1747-1756; Mukhopadhyay et al. (1999) J. Biol. Chem., 274:15978-15981); increased B cell proliferation (Moore et al. (1999) Science, 285:260-263); and increased survival of normally deleted B cells (Khare et al. (2000) Proc. Natl. Acad. Sci., 97:3370-3375; Gross et al. (2000) Nature, 404:995-999; Mackay et al. (1999) J. Exp. Med., 190:1697-1710). Three cognate receptors for BAFF have been identified: (1) B cell maturation antigen (BCMA; Accession No. S43486; Gross et al. (2000) Nature, 404:995-999; PCT Publication WO 01/12812; U.S. patent application Ser. No. 10/077,137); transmembrane activator and cyclophilin ligand interactor (TACI; Accession No. AAP57629; Gross et al., supra); and most recently, BAFFR (also called BR3; Accession No. AF373846; Thompson et al. (2001) Science, 293:2108-2111). BAFFR is the only one of the three receptors that is specific for BAFF (Thompson et al., supra). BCMA and TACI bind not only to BAFF but also to another TNF family ligand, APRIL (Yu et al. (2000) Nat. Immunol., 1:252-256; Wu et al. (2000) J. Biol. Chem., 275:35478-35485; Rennert et al. (2000) J. Exp. Med., 192:1677-1684; PCT Publication WO 01/24811; U.S. patent application Ser. No. 10/115,192).
While BAFF has been unambiguously identified as a factor required for B cell survival and maturation, the role of APRIL in B cell homeostasis remains less well understood. APRIL was originally found to stimulate growth of tumor cells in vitro and in vivo (Hahne et al. (1998) J. Exp. Med., 188:1185-1190). Recent reports demonstrated that APRIL may act also as a costimulator of primary B and T cells in vitro and stimulate IgM production by peripheral blood B cells in vitro (Yu et al. (2000) Nat. Immunol., 1:252-256; Marsters et al. (2000) Curr. Biol., 10:785-788). In vivo administration of APRIL, like BAFF, results in splenomegaly due to expansion of the B cell population and an increase in the percentage of activated T cells (Yu et al. (2000) Nat. Immunol., 1:252-256), suggesting that APRIL may be involved in lymphoid homeostasis. Based on data generated using APRIL-transgenic mice, APRIL appears to play a role in T cell-independent type 2 (TI-2) humoral responses (Stein et al. (2002) J. Clin. Invest., 109(12): 1587-1598). Further, data generated using A/WySnJ mice demonstrate that APRIL is not required for B cell development and function (Thompson et al., supra).
Soluble forms of BAFF receptors have been made by fusing their extracellular domains to the Fc portion of immunoglobulin. Treatment of normal mice with such a soluble form of TACI or BCMA (TACI-Fc or BCMA-Fc) leads to reduced B cell numbers and a lack of humoral response (Shu et al. (1999) J. Leukoc. Biol., 65:680-683; Yan et al. (2000) Nat. Immunol., 1:37-41; Xia et al. (2000) J. Exp. Med., 192:137-143; Wang et al. (2001) Nat. Immunol., 2:632-637; Yu et al. (2000) Nat. Immunol., 1:252-256). For example, in a mouse model for rheumatoid arthritis, an autoimmune disease that involves both B and T cell components, TACI-Fc substantially inhibits inflammation and slows disease progression (Wang et al. (2001) Nat. Immunol., 2(7):632-637). These effects are thought to be attributed to BAFF sequestration because BAFF-deficient mice have a phenotype similar to that of TACI-Fc- or BCMA-Fc-treated mice (almost complete loss of mature B cells and a severely compromised humoral response) (Schiemann et al. (2001) Science, 293:2111-2114; Gross et al. (2001) Immunity, 15:289-302). Although a five-week treatment of NZBWF1 with TACI-Ig lead to a reduction in SLE symptoms at 12 weeks after the treatment, no reduction in autoantibodies was observed, indicating that a longer course of treatment may be necessary (Gross et al. (2000) Nature, 404(6781):995-999).
Recently, BAFF-specific agents, including BAFFR-Fc and BAFF antibodies, have been developed for treatment of autoimmune and other disorders (see, e.g., U.S. patent application Ser. Nos. 09/911,777; 10/380,703; 10/045,574; and 60/458,707); Kalled et al. (2003) Expert Opin. Ther. Targets, 7(1):115-23). Once the administration of a BAFF-specific agent has ceased and the agent is eliminated from the bloodstream, B cell reconstitution to pre-treatment levels, including recovery of pathogenic B cells, is expected to occur within about 8 weeks (see, e.g., Porpiglia et al. (2003) Clin. Immunol., 107:90-97; Berardi et al. (1997) Blood, 89:3554-3564; Hiramatsu et al. (2003) Blood, 102:873-880). As a result, frequent administration of these drugs, at intervals of less than 8 weeks, may be necessary to maintain therapeutic benefits.
Therefore, new therapeutic strategies are still needed for the treatment of immune and related disorders.